We propose that the serotonin cells in the caudal brain stem, which project to the spinal cord, presynaptically inhibit primary afferent terminals of fibers carrying pain impulses. Furthermore, painful stimuli activate the noradrenergic cells of the locus coeruleus which project to and inhibit the bulbospinal raphe system. Finally, opiate analgesics inhibit the pain-induced activation of the locus coeruleus and permits the activation of raphe cells which produces presynaptic inhibition of pain impulses. This proposition will be tested by: (1) evaluating the response to pain and opiate analgesia in animals with lesions in the caudal raphe or the locus coeruleus; (2) stimulation of these nuclei to determine their influence on pain and opiate analgesia; (3) stimulating the locus coeruleus and recording the effects in raphe cells and (4) stimulating the caudal raphe nuclei and testing the effects on the transmission of pain impulses into the spinal cord.